Many studies have demonstrated that the hereditary nature of drug abuse is due to both genetic and environmental factors. Recent findings demonstrate that one mechanism regulating interactions between genes and the environment are epigenetic modifications. The term epigenetics refers to DNA and histone protein modifications that regulate gene expression and which are transmitted from a mother cell to a daughter cell or from a parent to a progeny, but which do not change the underlying DNA sequence. While it is clear that epigenetic modifications can be passed from one generation to the next, the mechanisms involved in the transmission of these effects are not fully understood. Several recent findings indicate that the maternal environment, both pre- and postnatal, may play a critical role in epigenetic transfer. To date, the role of epigenetics in familial patterns of drug abuse has not been well studied. Prescription narcotics use by adolescent females has increased dramatically in the past decade. We have developed an animal model of adolescent morphine exposure in female rats to examine the long-term consequences of opiate use during this unique developmental period. Our findings demonstrate that in addition to significant alterations in gene expression in adult female rats exposed to morphine during adolescence, the offspring of adolescent-exposed females demonstrate enhanced responsiveness to morphine. These offspring effects suggest adolescent morphine exposure increases the risk of drug abuse in the next generation. One of important aspect of this model is that adolescent morphine-exposed females are drug-free for at least 10 days prior to mating. Thus, developing offspring are never directly exposed to morphine. This means that any effect observed in the offspring is maternally-derived. The purpose of the present proposal is to determine the role of epigenetics in the long-term effects of adolescent morphine exposure on both the female and her offspring. The current proposal will identify transgenerational epigenetic modifications in the adult offspring of females exposed to morphine during adolescent development (Specific Aim 1). It will also examine possible changes in the maternal environment which may play a role in the transmission of these offspring effects (Specific Aim 2). Finally, we will test whether postnatal manipulations can ameliorate or prevent the transgenerational effects of adolescent morphine exposure (Specific Aim 3). Understanding how drug-induced alterations in morphine sensitivity may be passed from one generation to the next will help identify basic mechanisms underlying familial patterns of drug abuse as well as possible interventions. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand how mothers who are exposed to narcotics during adolescence increase the probability of drug abuse in their future offspring. These studies will provide a foundation for understanding the role of maternal factors in familial patterns of drug abuse.